Perspectives on PARPs in S Phase

• Published in: Trends in genetics 2019-06, Vol.35 (6), p.412-422
• Main Authors: Hanzlikova, Hana, Caldecott, Keith W.
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Cell Proliferation; Disease Susceptibility; DNA Damage; DNA Repair; DNA Replication; DNA replication stress; DNA strand break repair; Enzyme Activation; Genomic Instability; Humans; Molecular Targeted Therapy; Multigene Family; Okazaki fragment; PARP1; PARP2; poly(ADP-ribose); Poly(ADP-ribose) Polymerase Inhibitors - pharmacology; Poly(ADP-ribose) Polymerase Inhibitors - therapeutic use; Poly(ADP-ribose) Polymerases - genetics; Poly(ADP-ribose) Polymerases - metabolism; S Phase - physiology
• ISSN: 0168-9525
• DOI: 10.1016/j.tig.2019.03.008

Accurate copying of DNA during S phase is essential for genome stability and cell viability. During genome duplication, the progression of the DNA replication machinery is challenged by limitations in nucleotide supply and physical barriers in the DNA template that include naturally occurring DNA lesions and secondary structures that are difficult to replicate. To ensure correct and complete replication of the genome, cells have evolved several mechanisms that protect DNA replication forks and thus maintain genome integrity and stability during S phase. One class of enzymes that have recently emerged as important in this process, and therefore as promising targets in anticancer therapy, are the poly(ADP-ribose) polymerases (PARPs). We review here the roles of these enzymes during DNA replication as well as their impact on genome stability and cellular viability in normal and cancer cells. PARP1 and PARP2 are essential for embryonic viability, and chemical inhibition of these enzymes in the clinic selectively kills homologous recombination-defective cancer cells (e.g., those harbouring mutations in BRCA1 or BRCA2).PARP1 and PARP2 are activated by potentially pathogenic nucleic acid structures such as DNA breaks, DNA single-strand gaps, and stalled or broken DNA replication forks.PARP activity signals the presence of these structures by modifying themselves and other proteins with poly(ADP-ribose), thereby promoting their repair.Unligated Okazaki fragment DNA replication intermediates are primary inducers of PARP activity in normal proliferating cells.Unligated Okazaki fragments are candidate drivers of genome instability and/or cell death in developing embryos and in homologous recombination-defective cancer cells in which PARP activity is absent or inhibited.